In many diseases and conditions, a positive outcome of treatment and/or prophylaxis is strongly correlated with early and/or accurate diagnosis of the disease or condition. However, often there are no effective methods of early diagnosis and treatments are therefore often administered too late, inappropriately or to individuals who will not benefit from it. As a result, many drugs that may be beneficial for some patients may work poorly, not at all, or with adverse effect in other patients. Thus, there is a need for innovative strategies that will allow early detection, prediction, prognosis, diagnosis and treatment of diseases and other biological conditions. There is also a need to determine the ability, or inability, of a patient to tolerate medications or treatments.
Sepsis is more commonly called a blood stream infection or blood poisoning. It is the presence of bacteria (bacteraemia), infectious organisms, or their toxins in the blood or other tissues of the body. Sepsis often occurs in patients suffering from systemic inflammatory response syndrome (SIRS), as a result of e.g. surgery, trauma, burns, pancreatitis and other non-infectious events that cause inflammation to occur. SIRS combined with an infection is called sepsis and can occur in many different stages of severity. The infection can occur simultaneously with the occurrence of SIRS e.g. due to infection of a wound or trauma or can occur later due to the latent presence of an infectious organism. Sepsis may be associated with clinical symptoms of systemic (body wide) illness, such as fever, chills, malaise, low blood pressure, and mental status changes. Sepsis can be a serious situation, an often life threatening disease calling for urgent and comprehensive care. Treatment depends on the type of infection, but usually begins with antibiotics or similar medications.
As sepsis may be the result of infection by a wide variety of organisms it is a condition which is particularly difficult to predict and diagnose early enough for effective intervention. It is an excessive and uncontrolled inflammatory response in an individual usually resulting from an individual's inappropriate immune system response to a pathogenic organism. Moreover, there may not be significant numbers of organisms at accessible sites or in body fluids of the affected individual, thus increasing the difficulty of diagnosis. There is therefore a need to identify biomarkers indicating the risk, or early onset of sepsis, regardless of the causative agent, to allow early and effective intervention. Differentiating between patients who are at risk of developing sepsis and those who are not, will also assist in managing the disease condition. In particular, the ability to distinguish SIRS from sepsis in a patient is highly desirable, e.g. in a clinical setting for patients undergoing surgery or transplantation, suffering from trauma, etc which have to be monitored during and/or after their stay in the hospital.
There is therefore an immediate need for the identification of biomarkers that are measurable and specific for the condition, and indicative of the risk of progression to, or early onset of, sepsis as well as methods for using said markers in screening.
Biomarkers are biological indicators that signal a changed physiological state due to a disease or therapeutic intervention. It has been demonstrated that certain substances, including proteins and peptides, are expressed differentially in diseased tissue and bodily fluid samples in certain conditions such as sepsis, when compared to normal tissue and bodily fluid samples. Hence, differentially expressed protein/peptides(s) present in (or absent from) diseased samples from a patient, whilst being absent (or present) in normal tissue, is/are candidate biomarkers for that disease or condition.
Often a single biomarker alone may be insufficient for the accurate diagnosis of a disease or condition, especially one as complex as sepsis. As a result there is a continuing need for identification of biomarkers that may be used to identify or profile the condition at various stages in its pathology.
The only FDA-approved diagnostic biomarker for distinguishing sepsis from non-infectious causes of systemic inflammatory response syndromes (SIRS) currently available is Procalcitonin (PCT). The diagnostic and prognostic performance of PCT is however rather low as was shown in a recent report of Tang and co-workers (Tang B. M. J. et al., The Lancet vol 7:p 210-217, 2007), indicating that the procalcitonin test cannot accurately distinguish sepsis from SIRS in critically ill adult patients.
C-reactive protein is a further widely used marker for diagnosing sepsis, but is unable to distinguish between sepsis and SIRS without infection.
The inventors have now developed methods that enable rapid quantification, qualification and comparison of protein and peptide profiles derived from different biological samples and as a result have identified novel biomarkers for diagnosis, prognosis and/or prediction of sepsis and its different stages.